Variant 10-43197048-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_145313.4(RASGEF1A):c.1276G>T(p.Val426Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RASGEF1A
NM_145313.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

Variant links:

Genes affected

RASGEF1A (HGNC:24246): (RasGEF domain family member 1A) Enables guanyl-nucleotide exchange factor activity. Involved in cell migration and positive regulation of Ras protein signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

RASGEF1A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RASGEF1A	NM_145313.4 linkuse as main transcript	c.1276G>T	p.Val426Leu	missense_variant	11/13	ENST00000395810.6	NP_660356.2
RASGEF1A	NM_001282862.2 linkuse as main transcript	c.1300G>T	p.Val434Leu	missense_variant	11/13		NP_001269791.1
RASGEF1A	XM_005271809.4 linkuse as main transcript	c.1036G>T	p.Val346Leu	missense_variant	10/12		XP_005271866.1
RASGEF1A	XM_011539500.3 linkuse as main transcript	c.1036G>T	p.Val346Leu	missense_variant	10/12		XP_011537802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGEF1A	ENST00000395810.6 linkuse as main transcript	c.1276G>T	p.Val426Leu	missense_variant	11/13	1	NM_145313.4	ENSP00000379155	A1	Q8N9B8-1
RASGEF1A	ENST00000374459.5 linkuse as main transcript	c.1300G>T	p.Val434Leu	missense_variant	11/13	2		ENSP00000363583	P4	Q8N9B8-2
RASGEF1A	ENST00000395809.5 linkuse as main transcript	c.1276G>T	p.Val426Leu	missense_variant	11/13	2		ENSP00000379154	A1	Q8N9B8-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000110

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2024

The c.1276G>T (p.V426L) alteration is located in exon 10 (coding exon 10) of the RASGEF1A gene. This alteration results from a G to T substitution at nucleotide position 1276, causing the valine (V) at amino acid position 426 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

.;T;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.21

T;T;T

Sift4G

Uncertain

0.036

D;D;D

Polyphen

0.36

B;B;B

Vest4

0.71

MutPred

0.26

.;Gain of glycosylation at P429 (P = 0.2598);Gain of glycosylation at P429 (P = 0.2598);

MVP

0.58

MPC

0.79

ClinPred

0.97

GERP RS

5.0

Varity_R

0.44

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over